Short and long term dissemination of deletion mutants of adenovirus in permissive (cotton rat) and non-permissive (mouse) species

Abstract

As a first step in the evaluation of the safety of replication-defective adenoviruses used as gene transfer vectors, the dissemination of wild-type (wt) adenovirus (Ad) type 5, Ad-d1327 (deleted for the E3 gene) and Adgp50 (deleted for E3 and E1A and therefore replication defective) was studied in mice and cotton rats. Of each virus, 108 p.f.u, was inoculated, either by the intranasal or the intramuscular route, and virus isolation was undertaken after sacrifice of the animals 3 or 31 days after inoculation. E3 deletion had no significant effect on viral spread, whereas E1A deletion reduced it significantly. After intramuscular inoculation of the E3-/E1A-virus, it could be isolated only from the local lymph node. Intranasal inoculation led to a wider distribution including lungs, liver, kidneys and lymph nodes. The pattern of dissemination of the E3 -/E1A-virus was the same in mice and cotton rats, providing indirect evidence of the lack of replication of this virus in this species permissive for the wt virus. However, in the case of infection with a wt strain in E3-/E1A-adenovirus-inoculated recipients, both viruses were found in lymph nodes. In this situation the risk of phenotypic complementation of the E1A gene remains to be studied further.Adenovirus vectors are being used more and more widely for gene transfer, especially in non-dividing cells (Stratford-Perricaudet et al

Productive Replication of Human Adenoviruses in Mouse Epidermal Cells

“…At present, there is no immunocompetent mouse model to test replicating adenoviruses (2,11) as previous work suggests that both the infectivity and productive replication of adenoviruses in rodent cells are poor (4,9). In these model systems, although some evidence for limited replication has been obtained (12,17,18), a productive infection leading to an efficient viral burst has not been seen. This apparent block has been attributed to species-specific properties of mouse cells leading to repression of early viral protein expression (7) or defects at other points of the viral life cycle (5,16).…”

Adenovirus-mediated gene transfer into striated muscles

“…Similarly, recombination could take place if the adenovirus vector carrying a therapeutic gene is administered to a host with latent or manifested adenovirus infection by which the reactivation and escalation of the current adenovirus infection may happen. Replication and dissemination of the adenovirus vector can occur if a wild-type adenovirus acts as an incidental helper virus complementing the deleted El functions of the vector [120]. These problems could be prevented by the implementation of appropriate testing for the presence of adenovirus in the host prior the vector administration.…”

Mucosal immunization with recombinant adenoviruses: induction of immunity and protection of cotton rats against respiratory bovine herpesvirus type 1 infection.

“…Certain viruses, such as adenoviruses, may be unique in that they can induce long-term mucosal and systemic immune responses following mucosal administration. This may be associated with their ability to spread systemically (Huard et al, 1995 ;Oualikene et al, 1994) even though they primarily infect mucosal tissues.…”